(E)-ethyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)acrylate

General procedure: CuCl (1.5 mg, 0.015 mmol), NaOt-Bu (2.9 mg, 0.03 mmol), and Xantphos ligand (8.7 mg, 0.015 mmol) were placed in an oven-dried Schlenk tube under nitrogen and THF (0.45 mL) were added. The reaction mixture was stirred for 30 min at room temperature and then bis(pinacolato)diboron (127 mg, 0.5 mmol) in THF (0.3 mL) was added. The reaction mixture was stirred for 10 min and α, β-acetylenic ester 2 (0.5 mmol) was added, followed by MeOH (40 μL, 1 mmol). The reaction tube was washed with further THF (0.2 mL), sealed, and stirred until no starting material was detected by TLC. The reaction mixture was filtered through a pad of Celite and concentrated. The product was purified by silica gel chromatography.To a solution of 4-bromo-1-(2, 2, 2-trifluoroethyl)-1H-pyrazole (600 mg, 2.62 mmol) and ethyl (2E)-3 -(4, 4, 5, 5-tetramethyl- 1, 3 , 2-dioxaborolan-2-yl)acrylate (710 mg, 3.14 mmol, 1.2 eq) in 1, 4-dioxane (10 mL) was added potassium tert butoxide (587 mg, 5.2 mmol, 2.0 eq) and thereaction mixture was deoxygenated by purging nitrogen for 10 minutes. To this mixture was added (PPh3)4Pd (151 mg, 0.l3mmol, 0.15 eq) and mixture was again deoxygenated by purging nitrogen for 10 minutes. The reaction mixture was then allowed to stir under microwave at 140C for 1.5 h. Reaction mixture was cooled to RT, diluted with EtOAc (50 mL) and washed with brine (3 x 50 mL). Removal of solvent under reduced pressure gave crude which waspurified by Combi-flash on silica gel using EtOAc-hexane as eluent to afford ethyl (2E)-3-[4- bromo- 1 -(2, 2, 2-trifluoroethyl)- 1H-pyrazol-3 -yl]prop-2-enoate (400 mg, 61.34 %).To a solution of 4-bromo- 1 -(tetrahydro-2H-pyran-2-yl)- 1H-pyrazole (0.5 g, 2.16 mmol) in 1, 4-dioxane (6 mL) was added ethyl (E)-3-(4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl)acrylate (0.587 g, 2.59 mmol, 1.2 eq) and tert-butoxide (0.363 g, 1.5 eq) in water (3 mL) and the reaction mixture was deoxygenated using nitrogen gas for 10 minutes. Tetrakis(triphenylphosphine)palladium(0) (0.124 g, 0.10 mmol, 0.05 eq) was added and the reaction mixture was again deoxygenated for 10 minutes. Reaction mixture was allowed to stir at 140C for 1 h in microwave. Reaction mixture was cooled to RT, diluted with water (100 mL)and extract with ethyl acetate (3 x 20 mL). Combined organic layer was washed with brine (100 mL) and dried over anhydrous sodium sulfate. Removal of solvent under reduced pressure afforded crude which was purified by Combi-Flash to afford ethyl (E)-3-(1-(tetrahydro-2H- pyran-2-yl)-1H-pyrazol-4-yl) acrylate (0.3 g, 55.45 %)To a solution of 4-bromo-1-cyclopropyl-1H-pyrazole (0.5 g, 2.68 mmol) in dioxane (10 mL) was added ethyl (E)-3-(4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl)acrylate (0.73 g, 3.22 mmol, 1.2 eq) and potassium tert-butoxide (0.602 g, 5.37 mmol, 1.5 eq) in water (3 mL) and the reaction mixture was deoxygenated using nitrogen gas for 10 minutes. Tetrakis(triphenylphosphine)palladium(0) (0.154 g, 0.135 mmol, 0.05 eq) was added and the reaction mixture was again deoxygenated for 10 minutes. Reaction mixture was allowed to stir at 140C for 1 h in microwave. Reaction mixture was cooled to RT, diluted with water (50 mL) andextract using ethyl acetate (3 x 30 mL). Combined organic layer was washed with brine and dried over anhydrous sodium sulfate. Removal of solvent under reduced pressure afforded crude which was purified by Combi-Flash to afford ethyl (E)-3-(1-cyclopropyl-1H-pyrazol-4-yl) acrylate (0.370 g, 66.90 %).LCMS: 207 [M+1]To a solution of 4-bromo-3 , 5 -dimethyl- 1 -(tetrahydro-2H-pyran-2-yl)- 1 H-pyrazole (0.5 g, 2.86 mmol) in dioxane (6 mL) was added ethyl (E)-3-(4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2- yl)acrylate (0.77 g, 3.42 mmol, 1.2 eq) and tert-butoxide (0.48 1 g, 1.5 eq) in water (3 mL) andthe reaction mixture was deoxygenated using nitrogen gas for 10 minutes. Tetrakis(triphenylphosphine)palladium(0) (0.165 g, 0.14 mmol, 0.05 eq) was added and the reaction mixture was again deoxygenated for 10 minutes. Reaction mixture was allowed to stir at 140 C for 1 h in microwave. Reaction mixture was cooled to RT, diluted with water (50 mL) and extract using ethyl acetate (3 x 20 mL). Combined organic layer was washed with brine anddried over anhydrous sodium sulfate. Removal of solvent under reduced pressure afforded crude which was purified by Combi-Flash to afford ethyl (E)-3-(3, 5-dimethyl-1-(tetrahydro-2H-pyran- 2-yl)-1H-pyrazol-4-yl)acrylate (1.2 g).To a solution of 6-bromo-2, 3-dihydro-[1, 4]dioxino[2, 3-b]pyrazine (250 mg, 1.15 mmol, eq) in a mixture of 1, 4-dioxane (5 mL) and H20 (2 mL) were added (E)-ethyl 3-(4, 4, 5, 5- tetramethyl-1, 3, 2-dioxaborolan-2-yl)acrylate (312.6 mg, 1.38 mmol, 1.2eq) and t-BuOK (193.91 mg, 1.72 mmol, 1.5 eq) at room temperature. The reaction mixture was deoxygenated by purging nitrogen for 5 minutes. To this mixture was added (Ph3P)4Pd (66.6 mg, 0.05 mmol, 0.05eq) and mixture was again deoxygenated by purging nitrogen for 10 minutes. The reaction mixture was stirred at 140C under microwave for 1 h. Progress of reaction was monitored by TLC. After completion, reaction mixture was diluted with water (50 mL) and extract with ethyl acetate (3 x 50 mL). Combined organic layer was washed with brine and dried over anhydrous sodium sulfate. Removal of solvent under reduced pressure afforded crude which was purified byCombi-Flash on silica gel using ethyl acetate-hexane system as eluent to afford (E)-ethyl 3-(2, 3- dihydro-[ 1 , 4]dioxino[2, 3 -b]pyrazin-6-yl)acrylate (170 mg, 62.73 %)

Molecular Weight:226.08
Hydrogen Bond Acceptor Count:4
Rotatable Bond Count:4
Exact Mass:226.1376392
Monoisotopic Mass:226.1376392
Topological Polar Surface Area:44.8
Heavy Atom Count:16
Complexity:280
Defined Bond Stereocenter Count:1
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes